ABSTRACT

The maternal epigenome may be responsive to prenatal metals exposures. We tested whether metals are associated with concurrent differential maternal whole blood DNA methylation. In the Early Autism Risk Longitudinal Investigation cohort, we measured first or second trimester maternal blood metals concentrations (cadmium, lead, mercury, manganese, and selenium) using inductively coupled plasma mass spectrometry. DNA methylation in maternal whole blood was measured on the Illumina 450 K array. A subset sample of 97 women had both measures available for analysis, all of whom did not report smoking during pregnancy. Linear regression was used to test for site-specific associations between individual metals and DNA methylation, adjusting for cell type composition and confounding variables. Discovery gene ontology analysis was conducted on the top 1,000 sites associated with each metal. We observed hypermethylation at 11 DNA methylation sites associated with lead (FDR False Discovery Rate q-value <0.1), near the genes CYP24A1, ASCL2, FAT1, SNX31, NKX6-2, LRC4C, BMP7, HOXC11, PCDH7, ZSCAN18, and VIPR2. Lead-associated sites were enriched (FDR q-value <0.1) for the pathways cell adhesion, nervous system development, and calcium ion binding. Manganese was associated with hypermethylation at four DNA methylation sites (FDR q-value <0.1), one of which was near the gene ARID2. Manganese-associated sites were enriched for cellular metabolism pathways (FDR q-value<0.1). Effect estimates for DNA methylation sites associated (p < 0.05) with cadmium, lead, and manganese were highly correlated (Pearson ρ > 0.86). DNA methylation sites associated with lead and manganese may be potential biomarkers of exposure or implicate downstream gene pathways.

摘要

母体表观基因组可能对产前金属暴露有反应。我们测试了金属是否与同时存在差异的母体全血 DNA 甲基化有关。在早期自闭症风险纵向调查队列中，我们使用电感耦合等离子体质谱法测量了孕早期或孕中期母体血液中的金属浓度（镉、铅、汞、锰和硒）。在 Illumina 450 K 阵列上测量母体全血中的 DNA 甲基化。97 名妇女的子集样本具有可用于分析的两种测量方法，所有这些妇女都没有报告怀孕期间吸烟。线性回归用于测试单个金属和 DNA 甲基化之间的位点特异性关联，调整细胞类型组成和混杂变量。Discovery基因本体分析在top 1上进行，000 个与每种金属相关的位点。我们观察到与铅相关的 11 个 DNA 甲基化位点的高甲基化（FDR 错误发现率q -值 <0.1)，靠近基因CYP24A1、ASCL2、FAT1、SNX31、NKX6-2、LRC4C、BMP7、HOXC11、PCDH7、ZSCAN18和VIPR2。对于细胞粘附、神经系统发育和钙离子结合的途径，铅相关位点富集（FDR q值 <0.1）。锰与四个 DNA 甲基化位点 (FDR q -value <0.1) 的高甲基化有关，其中一个位于基因ARID2附近。锰相关位点富含细胞代谢途径（FDR q -值<0.1）。相关 DNA 甲基化位点的效应估计 ( p < 0.05) 与镉、铅和锰高度相关 (Pearson ρ > 0.86)。与铅和锰相关的 DNA 甲基化位点可能是潜在的暴露生物标志物或涉及下游基因途径。